1. Field of the Invention
The present invention relates to a bifunctional material comprising a zeolite which is capable of releasably absorbing nitric oxide and producing nitric oxide from a suitable precursor molecule.
2. Background Art
Storage of gases in tailored porous materials is an extremely important technology with great potential for impact in a wide variety of applications, from energy storage and environmental remediation to biological/medical devices. The gases of interest encompass hydrogen (N. L. Rosi, J. Eckert, M. Eddaoudi, D. T. Vodak, J. Kim, M. O'Keeffe, O. M. Yaghi Science, 300, 1127, (2003)), various different hydrocarbons (M. Eddaoudi, J. Kim, N. Rosi, D. T. Vodak, J. Wachter, M. O'Keeffe, O. M. Yaghi, Science, 295, 469, (2002); R. Matsuda, R, Kitaura, S. Kitagawa, Y. Kubota, R. V. Belosludov, T. C. Kobayashi, H. Sakamoto, T. Chiba, M. Takata, Y. Kawazoe, Y. Mita, Nature 436, 238, (2005)), carbon dioxide (A. R. Millward, O. M. Yaghi, J. Am Chem Soc. 127 17998 (2005)) and nitric oxide (Keefer, L. K. Nature Materials, 2, 357 (2003); P. S. Wheatley, A. R. Butler, M. S. Crane, B. Xiao, A. G Rossi, I. L. Megson R. E. Morris, J. Am Chem Soc. 2006, 128, 502-509). A major drawback of gas storage materials is the finite reservoir of gas that is available—eventually even the highest capacity materials will run out of the stored gas, no matter how slowly it is delivered for use. For some applications, where recharging the material with the required gas is relatively easy or if the material is completely replaced with a new gas loaded sample, this may not be of too much concern. However, where the gas storage material needs to be in place for a long time, the limited lifetime of stored gas may be a significant handicap. A prime example of a situation where this could be vitally important is the use of nitric oxide (NO) releasing materials in medical devices or implants that need to remain in situ for days, months or even years. In such cases, NO release needs to last an equally long time to ensure that the beneficial effects continue. With simple gas storage materials, this is unlikely to be possible.
NO is an extremely important signalling molecule in mammalian biology, and there is increasing evidence that exogenously applied NO is beneficial in a number of areas, including the prevention of thrombosis, the promotion of wound healing and anti-microbial therapies.
The present inventors have recently showed how zeolites (porous alumino silicate materials) can be used to store and deliver NO in biologically important amounts (P. S. Wheatley, A. R. Butler, M. S. Crane, B. Xiao, A. G Rossi, I. L. Megson R. E. Morris, J. Am Chem Soc. 2006, 128, 502-509)). This work showed how, zeolites irreversibly adsorb large amounts of NO, which is only released on the action of a trigger such as exposure to moisture. The storage lifetime of NO in zeolites is long term (no loss of NO delivery even after 1 year's storage) and can be tailored for a particular application by altering the composition of the zeolite or by blending the zeolites with appropriate polymer matrices. The use of zeolites as water softeners in detergent powder formulations also means that their toxicology is relatively well studied, at least in terms of topical exposure.
However, for biological applications it is not the storage capacity of the material that is the most important feature, but the match between the rate and duration of delivery and that required by the target application. NO is produced by the endothelial cells that line normal healthy blood vessels at a rate that has been estimated to be ˜1 pmol min−1 mm−2 and this mediates a number of vital functions including vasodilatation (Furchgott, R. F.; Zawadzki, J. V., Nature 1980, 288, 373; Palmer, R. M. J.; Ferrige, A. G.; Moncada, S. Nature 1987 327, 524), prevention of vascular smooth muscle growth and inhibition of platelet (Radomski, M. W.; Palmer, R. M. J.; Moncada, S., Lancet 1987, 2, 1057) and inflammatory cell (Bath, P. M. W.; Hassall, D. G.; Gladwin. A. M.; Palmer, R. M. J.; Martin, J. F., Arterioscler. Thromb. 1991, 11, 254; Kubes, P.; Suzuki, M.; Granger, D. N., Proc. Natl Acad. Sci, USA. 1991, 87, 5193) activation and adhesion. To mimic the action of endothelial NO on the surface of a medical implant such as a stent requires a relatively low rate of NO delivery over a considerable period of time. However, NO also has an anti-microbial effect, and larger amounts of NO prevent biofilm formation and can be used to kill many different organisms, even resistant bacterial strains such as MRSA (A. GhaVari, C. C. Miller, B. McMullin, A. Ghahary, Nitric Oxide 14, 21, (2006); see the international zeolite association website www.iza-online.org for details of how the codes relate to the framework structures of the zeolites). Since many failures of medical implants can be traced back to infection (B. J. Nablo, H. L. Prichard, R. D. Butler, B. Klitzman, M H. Schoenfisch, Biomaterials 26, 6984 (2005)) this anti-microbial action of NO is also very desirable, and could be performed by a short burst (minutes to hours) of NO on first use of the implant. A material that delivers a burst of NO followed by a steady release of NO at a lower level maybe the optimum behaviour for medical applications of this type. It is expected that it will be impossible to obtain such a release profile from simple stored NO and as such there is a requirement for novel materials designed to address the above problems.
It is therefore amongst the objects of the present invention to obviate and/or mitigate at least one of the aforementioned disadvantages.
It is a further object of the present invention to provide a bifunctional product which is capable of storing NO and also producing NO from a precursor material.